Scleroderma in Children: Emerging Management Issues PDF Print E-mail
Tuesday, 27 July 2010 23:02
Saumya Panda
Department of Dermatology, KPC Medical College, Kolkata, India
Date of Web Publication: 21-Jul-2010

Scleroderma is a set of rare connective tissue diseases of unknown etiology. It is characterized by thickening and hardening of the skin. Scleroderma is divided into two main subgroups: systemic and localized. The systemic form, also known as systemic sclerosis, involves diffuse skin involvement associated with fibrotic changes in internal organs. Juvenile localized scleroderma is a more common entity and is usually confined to a specific region of the body with no internal organ involvement. Therapeutics are divided into three main subgroups for juvenile systemic sclerosis: antifibrotics, anti-inflammatories, and vasodilators. For localized disease, anti-inflammatories, vitamin D analogues, and UV irradiation have been investigated. The rarity of scleroderma in children and the self-limiting nature of the disease together make randomized controlled trials very difficult. Therefore, most data on therapeutic modalities for this condition have to be extrapolated from studies conducted on adults. International cooperation, following a standardized operation protocol, is needed to validate these and future interventions such as autologous stem cell transplant and cytokine-directed therapies.

Scleroderma is a set of rare and complex connective tissue diseases of unknown etiology. They encompass a range of clinical characteristics that result from excess collagen deposition in tissues leading to fibrosis. Scleroderma is classified into two major subtypes: systemic and localized.

Juvenile Systemic Sclerosis         
Juvenile systemic sclerosis (JSSc) is a chronic multisystemic connective tissue disorder characterized by symmetrical thickening and hardening of the skin, associated with fibrous changes in internal organs. Although rare in children, it represents one of the most severe rheumatic conditions in pediatric rheumatology practice. Recently, a Committee on Classification Criteria for JSSc, including members of the Pediatric Rheumatology European Society (PRES), the American College of Rheumatology (ACR), and the European League Against Rheumatism (EULAR), developed a new classification criteria to help standardize the conduct of clinical, epidemiological, and outcome research for this rare pediatric disease. These criteria, which will supplant the adult criteria that have been used until now, will help ensure an accurate diagnosis of JSSc.

Children under 16 years of age account for less than 5% of all cases of JSSc. Peak age of onset is between 10 and 16 years. In an Indian study, the mean age at presentation was 17 years. The disease is almost fourfold more frequent in girls. Raynaud's phenomenon (RP) is the first sign of the disease in 70% of the patients, and in 10% it is complicated by digital infarcts. Proximal skin induration is the second most frequent symptom, being present in 40% of cases.

The pharmacologic management of patients who have JSSc is challenging, because no drug has been shown to be of unequivocal benefit in either children or adults who have systemic sclerosis. Patients with scleroderma require different therapeutic approaches depending on whether their disease is in an 'active' inflammatory stage, or a later 'irreversible' stage with fibrosis, but no active inflammation. The main treatment modalities currently used are antifibrotics, immunosuppressive agents, and vasodilators. Several organ-specific therapies are also employed.

Antifibrotic agents: Massive deposition of collagen and other newly synthesized connective tissues leading to fibrosis may lead to organ failure in diffuse cutaneous systemic sclerosis (dcSSc). Antifibrotic agents have not been very successful in treating dcSSc.

Penicillamine is the oldest of the commonly used antifibrotic agents, but has lost favor among most rheumatologists. It has been used to treat dcSSc for several decades, but with questionable efficacy. In uncontrolled case series, penicillamine was beneficial, resulting in skin softening, a reduction of new visceral involvement, and improved survival. A double-blind randomized controlled clinical trial concluded that low-dose penicillamine (125 mg alternate days) was of equivalent efficacy with that of high-dose administration (750-1000 mg/day) of the drug. There are only anecdotal reports of penicillamine efficacy in children, and it is not commonly used any longer.

Interferon-γ is a cytokine that has been shown to reduce collagen production and interfere with fibroblast proliferation by downregulating the expression of transforming growth factor-β (TGFβ).  However, it has not been shown to be very effective and has a high incidence of adverse reactions, and is therefore not commonly used.

Another agent with a potential antifibrotic effect is relaxin, a pregnancy polypeptide cytokine growth factor that decreases the synthesis of interstitial collagens and blocks TGFβ in vitro. Intially, this treatment showed promise in a randomized, double-blind, parallel-group, placebo-controlled, multicenter clinical trial, but a phase II trial of relaxin was negative and this treatment option was abandoned.

Imatinib mesylate, a potent inhibitor of TGFb as well as platelet-derived growth factor (PDGF), and thus the synthesis of extracellular matrix (ECM) proteins, has been shown to prevent experimental dermal fibrosis, thereby holding out new hope for antifibrotic management in systemic sclerosis.

Immunosuppressive agents: Methotrexate, which is used widely for the treatment of many rheumatic conditions in children, has been shown to improve skin score in early dcSSc in adults. A randomized controlled trial in early diffuse scleroderma in adult patients done in India showed that methotrexate produces a slight favorable effect, particularly on the skin scores; however, it is not sustained after 12 months. Children tend to tolerate higher doses of methotrexate well and have very little toxicity associated with it. According to a pediatric SSc experts' opinion, methotrexate could be the treatment of choice for the skin manifestations of children who have JSSc, especially in the early phase. All children receiving methotrexate should be mentioned for adverse effects such as liver toxicity, pulmonary fibrosis and cytopenias.

Cyclosporin is a medication occasionally used to treat dcSSc in adults, but is more frequently used in children. Cyclosporin blocks the transcription of messenger RNA for several immnue-activating and proinflammatory cytokines (e.g. interleukin (IL)-2) that are elevated in dcSSC. All trials of cyclosporin for dcSSc have been performed in adults. There continue to be reports of cyclosporin being used in children with dcSSc, though there have been no organized trials. As with all medications, children should be monitored closely for adverse effects such as renal insufficiency and hypertension.

Glucocorticoids, preferably prednisone at a dosage of 0.3-0.5 mg/kg/d, have very few indications in JSSc; indications include the treatment of myositis, arthritis and tenosynovitis. Several studies suggest that steroids are associated with a higher risk of scleroderma renal crisis. Therefore, patients on steroids should be monitored carefully for blood pressure and renal function.

Despite the modest benefits claimed in recently published studies, and despite its known toxicity, an EULAR task force of 18 SSc international experts have recently opined that cyclophosphamide should be considered for the treatment of SSc-related interstitial lung disease in children. As in juvenile systemic lupus erythematosus, cyclophosphamide should be administered as intravenous pulse therapy at a dosage of 0.5 to 1g/m 2 every four weeks for at least six months. Adequate hydration and frequent voiding must be emphasized to prevent cystitis. Prophylatic MESNA should be considered to minimize contact of acrolein with the bladder mucosa.

UVA-1 phototherapy has recently showed some promise for treating the sclerotic skin lesions of systemic sclerosis, but its use in children is limited due to concerns about carcinogenicity; however, currently UVA-1 is considered less carcinogenic than psoralen plus UVA (PUVA).

Intravenous immunoglobulin (IVIg) has been recently used as an immunomodulator and has been shown to reduce skin fibrosis in systemic sclerosis. Likewise, tumor necrosis factor (TNF)-alpha blockers, notably infliximab and etanercept, have been investigated in recent years in diffuse scleroderma and has shown marginal clinical improvement, especially of skin involvement. Prominent among other biologics to be used with some success in systemic sclerosis is rituximab, the CD-20 positive B-cell antagonist.

Vasodilators: Vasodilators are used to reduce vasospasm (Raynaud phenomenon, RP) and to improve peripheral circulation in children with dcSSc. Although used regularly, those have been no trials of vasodilator treatments in children with scleroderma.

Calcium channel antogonists (CCA) are the vasodilators most often used to treat dcSSc. These drugs inhibit smooth muscle contraction by reducing the cellular uptake of calcium. Two groups of CCAs have been used: the pyridine dicarboxylic acids (nifedipine and nicardipine) and the dimethoxyphenyls (verapamil and diltiazem). Amlodipine is a newer agent that is being increasingly used. Oral CCAs should be considered as first-line therapy for RP.

Angiotensin II receptor inhibitors (e.g., losartan) have also been found to have benefit in the treatment of RP. Angiotensin converting enzyme (ACE) inhibitors (e.g., captopril) are unanimously considered to be effective for the long-term control of blood pressure and stabilization of renal function of scleroderma renal crisis.

Prostacyclin analogues, intravenous prostanoids that is, are used for severe SSc-related RP and digital ulcers. Intravenous epoprostenol is a potent vasodilator produced by endothelial cells that acts through activation of membrane-bound adenylate cyclase to increase cyclic adenosine monophosphate (cAMP). Iloprost (carboprostacyclin) is a chemically stable prostacyclin analogue. It is a potent vasodilator and has been shown to decrease connective tissue growth factor (CTGF) levels. A recent study in children who had JSSc and other connective tissue diseases reported that intermittent infusions of iloprost was safe and effective in treatment of refractory RP and ischemic digits.

Some recommendations for symptomatic treatment are essentially based on the principle of good clinical practice. These include the use of:
  • Proton pump inhibitors (PPIs), such as omeprazole and lansoprazole, for preventing gastroesophageal reflux disease (GERD) and esophageal ulcers.
  • Prokinetic drugs, such as domperidone, for managing symptomatic dysmotility.
  • Rotating antibiotics, such as metronidazole, ciprofloxacin, and doxycycline, to treat malabsorption caused by bacterial overgrowth. [4]

Future therapies: Bosentan, a dual endothelin receptor antagonist, is a novel agent being experimented in pulmonary arterial hypertension (PAH), which carries the worst prognosis of any organ involvement in systemic sclerosis. This agent targets endothelin-1, a peptide with vasoconstrictive effects. Novel agents with vasodilator properties, like sitaxsentan and sildenafil, are being investigated for digital ulcers. Pediatric experts have expressed interest for future applications of these agents in pediatric clinical trials, although there is not enough experience, at present, to recommend their use. Other than these, several agents and classes of therapy are being investigated in adults; there is no idea, however, if and when these will be applicable in pediatric patients.

Conclusion: Compared with adult-onset disease, JSSc appears to be less severe with less organ involvement and to have less specific autoantibody profile and better long-term outcome. Many of the recommendations for the management of SSc in adults can be extended to the childhood-onset SSc. A few of the studies and trials on SSc mentioned in this review have been summarized along with their levels of evidence

Juvenile Localized Scleroderma         
Juvenile localized scleroderma (JLS), also known as morphea, consists of a group of conditions that involve essentially the skin and subcutaneous tissues. JLS is much more common than systemic sclerosis in childhood, by a ratio of at least 10:1. No studies have assessed the prevalence of this disease, but it is believed to occur in up to 1 per 100,000. There is a mild female predilection (female to male ratio 2.4:1). The mean age at disease onset is 7.3 years, and a few cases with onset at birth, so called congenital localized scleroderma, have been described.

Most commonly JLS is divided into five general types: plaque morphea, generalized morphea, bullous morphea, linear scleroderma and deep morphea. A new classification has been proposed including the following five subtypes: circumscribed morphea (CM), linear scleroderma, generalized morphea (GM), pansclerotic morphea and the mixed subtype where a combination of two or more of the other subtypes is present. JLS patients who have extracutaneous manifestations represent a new subset of JLS.

Investigational tools: Clinical examination in JLS being subjective, and classical skin scoring methods, viz., the modified Rodnan score used in systemic sclerosis being not applicable, the detection of disease activity remains a fundamental problem, that is now sought to be addressed by a few novel tools that, however, need to be validated.

Infrared thermography (IRT), that is of value in the detection of active JLS, has a very high reproducibility but low specificity, particularly in the assessment of older lesions. In the latter, laser Doppler flowmetry (LDF) can help discriminate real active lesions from false-positive changes. A computerized skin score (CSS) method for measuring circumscribed lesions in LS has been recently proposed. CSS has been shown to have very low intra- and interobserver variability. Magnetic resonance imaging (MRI) is also an important tool, particularly when central nervous system (CNS) or eye involvement is suspected, as also to demonstrate the true depth of soft tissue lesions.

In addition, there is evidence to suggest that laboratory measures such as eosinophilia, hypergammaglobulinemia or elevated ESR are signs of active disease.

Therapy: JLS is a very slow, progressive disease. The usual natural history is to remit spontaneously over time. However, it may result in severe morbidity as well, limiting range of motion, atrophying the limb or face, deforming growth and causing leg length discrepancy Unfortunately, the rarity of this condition and the difficulty in assessing outcome in an objective manner have limited the interpretation of most clinical studies. As a result, no guidelines have emerged till now for the disease. In this scenario, the key determination is the level of discomfort (cosmetic or functional) associated with the developing lesion, which must be balanced against the risks of therapy.

Physiotherapy plays a major part in the management of LS, particularly in lesions involving articular structures. However, no published studies have documented this therapy.

Topical therapy is indicated for lesions that neither involve the deeper structures nor are associated with significant cosmetic disability. Emollients are marginally effective in this setting.  Topical corticosteroids may be of some use during the inflammatory stage and in circumscribed morphea, but long-term use may cause subcutaneous atrophy. Intralesional corticosteroids have also been tried in JLS. Topical tacrolimus 0.1% ointment has been used for the treatment of early inflammatory morphea with some success. In a clinical trial involving seven patients for three months, lesions treated with occlusive tacrolimus for 12 h at night, resulted in softening and reduced inflammatory infiltrate in all patients one month after treatment. Topical calcipotriene (calcipotriol) has also been tried in CM. Cunningham et al, evaluated the efficacy of calcipotriene ointment 0.005% in an open study of 3 months duration in 12 patients between 12 and 38 years of age. At the end of the study, the authors observed significant improvement of cutaneous induration in all patients and a lack of side effects and abnormalities in mineral metabolism. Good results have been reported recently with topical imiquimod, a novel immunomodulator that upregulates interferons a and g, thereby downregulating TGFb and inhibiting collagen production by fibroblasts.

Despite the lack of knowledge on risks and benefits, vitamin D and its analogues (viz. calcitriol) have been utilized systemically in some studies of LS with mixed results. A randomized controlled trial of 20 adult patients with LS did not demonstrate efficacy of oral calcitriol. However, in a study of seven children with LS treated with oral calcitriol (0.25-1.25 μg/day), five had skin improvement. No adverse effects were observed during a follow-up period of 4-20 months.

Phototherapy with ultraviolet (UV) rays represents another therapeutic possibility in LS. Treatment with UVA1 at low, medium, and high doses, without or with psoralens (PUVA) all seem to be effective clinically, though high doses seem somewhat better. Phototherapy appears to be much more effective for localized or superficial lesions. Although no controlled studies have been published, excellent results have been reported with PUVA treatment in patients with localized scleroderma. Pasic et al, reported the treatment of six children with photochemotherapy with PUVA baths with good results, showing softening of sclerotic plaques. The results were obtained with a small number of sessions (14-39, mean 25). Grundmann-Kollmann et al, showed that topical PUVA induced significant improvement in 4 patients treated 4 times a week, totaling up to 30 sessions. Because the rate of relapse after UV phototherapy discontinuation is not known, the need for prolonged maintenance therapy, leading to a high cumulative dosage of irradiation, and the increased risk for potential long-term effects such as skin aging and carcinogenesis are clear limitations for its use in the pediatric age group.

When there is a significant risk of disability, such as in linear and deeper subtypes, methotrexate (MTX) in combination with systemic corticosteroids should be considered. The treatment protocol usually consists of a combination of oral prednisolone or intravenous methylprednisolone (IVMP 20-30 mg/kg/d for 3 days) and MTX (10-15 mg/m 2 /wk). Most patients show a response within two to four months, and the adverse effects are usually mild and associated more with steroid use rather than with MTX. Unfortunately, the studies have not been controlled trials, and the series of treated patients very small.

Penicillamine appears to affect collagen metabolism and has been used to treat localized scleroderma for a long time. Moynahan reported uniformly good results in all 14 children treated with low-dosage penicillamine (150-450 mg/day) with no adverse effects. These results have been fairly corroborated by later studies as well.

Conclusion: JLS is an uncommon challenging disorder. The rarity of scleroderma in the pediatric population plus the fact that this disease is very often self-limiting makes randomized controlled trials very difficult. It is for this reason that most data on treatment modalities for this disease have been extrapolated from studies in adult patients. There is no single therapy for JLS that has proven to be very effective or significantly disease modifying. However, current therapeutic strategies must be initiated early in the disease course for maximally beneficial clinical effects. The close collaboration among pediatricians, rheumatologists and dermatologists represents an important advance in the management of this disabling condition.

Source: Indian Journal Of Dermatology
For more information on Juvenile Scleroderma, we encourage you to visit the Juvenile Scleroderma Network

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